Discovery of renin inhibitors containing a simple aspartate binding moiety that imparts reduced P450 inhibition

Article abstract of DOI:10.1016/j.bmcl.2017.09.046

Discovery of potent renin inhibitors which contain a simplified alkylamino Asp-binding group and exhibit improved selectivity for renin over Cyp3A4 is described. Structure-function results in this series are rationalized based on analysis of selected compounds bound to renin, and the contribution of each molecular feature leading to the reduced P450 inhibition is quantified.

Full text of DOI:10.1016/j.bmcl.2017.09.046

Accepted Manuscript
Discovery of renin inhibitors containing a simple aspartate binding moiety that
imparts reduced P450 inhibition
Brian G. Lawhorn, Tritin Tran, Victor S. Hong, Lisa A. Morgan, BaoChau T.
Le, Mark R. Harpel, Larry Jolivette, Elsie Diaz, Benjamin Schwartz, Jeffrey W.
Gross, Thaddeus Tomaszek, Simon Semus, Nestor Concha, Angela Smallwood,
Dennis A. Holt, Lara S. Kallander
PII:
S0960-894X(17)30954-X
https://doi.org/10.1016/j.bmcl.2017.09.046
BMCL 25310
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 September 2017
20 September 2017
22 September 2017
Please cite this article as: Lawhorn, B.G., Tran, T., Hong, V.S., Morgan, L.A., Le, B.T., Harpel, M.R., Jolivette, L.,
Diaz, E., Schwartz, B., Gross, J.W., Tomaszek, T., Semus, S., Concha, N., Smallwood, A., Holt, D.A., Kallander,
L.S., Discovery of renin inhibitors containing a simple aspartate binding moiety that imparts reduced P450 inhibition,
Bioorganic & Medicinal Chemistry Letters (2017), doi: https://doi.org/10.1016/j.bmcl.2017.09.046
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Bioorganic & Medicinal Chemistry Letters
Discovery of renin inhibitors containing a simple aspartate binding moiety that
imparts reduced P450 inhibition
Brian G. Lawhorna,*, Tritin Trana, Victor S. Honga, Lisa A. Morgana, BaoChau T. Lea, Mark R. Harpela,
Larry Jolivettea, Elsie Diazb, Benjamin Schwartzb, Jeffrey W. Grossb, Thaddeus Tomaszekb, Simon Semusb,
Nestor Conchab, Angela Smallwoodb, Dennis A. Holta, Lara S. Kallandera
aHeart Failure DPU, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pa 19406, USA
bPlatform Sciences and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pa 19426, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Discovery of potent renin inhibitors which contain a simplified alkylamino Asp-binding group
and exhibit improved selectivity for renin over Cyp3A4 is described. Structure-function results
in this series are rationalized based on analysis of selected compounds bound to renin, and the
contribution of each molecular feature leading to the reduced P450 inhibition is quantified
Accepted
Available online
2017 Elsevier Ltd. All rights reserved.
Keywords:
Renin inhibitors
Cyp3A4
biphenyl
hypertension
x-ray crystallography
As the first and rate-limiting enzyme in the renin-angiotensin
system, renin has been heralded as an optimal target for the
regulation of hypertension, and clinical success in this area has
recently been achieved with aliskiren, the first FDA approved
renin inhibitor.1 Although aliskiren effectively reduces blood
pressure at levels comparable to the ARBs and ACE inhibitors,
and is capable of producing additional positive blood pressure
effects in combination with these agents, the drug suffers from
the drawbacks typically associated with renin inhibitors (poor
bioavailability, cost of synthesis).1 As a result of these
limitations, efforts to develop alternative renin inhibitors
continue across the pharmaceutical industry in both the clinical
and pre-clinical settings.2
A series of biphenylpiperidinylcarbinol renin inhibitors (1,
Figure 1) derived from structure-based design was previously
disclosed by Vitae Pharmaceuticals with whom we partnered to
discover new renin inhibitors within this class.3 The more active
members of this class feature three common motifs: 1) a
substituted biphenyl group which occupies both the S1 and S3
hydrophobic binding pockets of renin, 2) a methyl propyl
carbamate moiety that fills and forms hydrogen bonds within the
deep, narrow S3sp binding site, and 3) an alkylamino
functionality that forms a hydrogen-bonded salt bridge with the
catalytic aspartate residues (Asp32 and Asp215) of renin.4 By
design, a (1R,3S)-3-aminocyclopentyl moiety was selected to
display the Asp-binding amino group in this series, as structural
evidence suggested that the cyclopentane ring would present the
amino group in an optimal alignment for Asp binding without
inducing unfavorable conformations.
Impressively, this
analogue design produced exceptionally potent renin inhibitors
(e.g. 1b, renin IC50 < 1 nM, PRA IC50 < 5 nM based on GSK
assays, see Supporting Information) which are on par with
aliskiren. However, the prototypical members of this series
contain shortcomings that could limit their usefulness in clinical
development of new anti-hypertensive agents. Of particular
concern is the potent inhibition of cytochrome P450 3A4
(Cyp3A4) that accompanies this class, the synthetic complexity
required to assemble these molecules, and their poor oral
bioavailability.
Herein, we disclose the discovery of potent renin inhibitors
derived from compound 1 which contain simplified alkylamino
Asp-binding groups. The optimal compounds in the series,
which inhibit renin activity at levels comparable to 1a, exhibit
43-fold greater selectivity against Cyp3A4 when measured under
identical assay conditions (see Supporting Information).
A
comparison of key analogues reveals that the moderate P450
activity arises in part from N-methylation (~2-fold effect) and to
a greater extent from the reduced lipophilic nature (~20- fold
effect) of this compound series.
Structures of selected
compounds bound to renin are presented and used to rationalize

the structure-function information generated during the course of
the investigation.
determine their Cyp3A4 inhibition within a biological matrix (see
Supporting Information).
In an effort to decrease the complexity of 1a, and with the
intent of reducing the lipophilicity of the renin inhibitors, n-
alkylamines were screened as potential replacements for the Asp-
binding cyclopentylamine moiety (3a-e, Table 1). Compounds
bearing C1C5 alkylamines displayed good to moderate activity
against renin (IC50 = 1100 nM), and the propylamine group
emerged as an effective substitution with 3c displaying similar
potency against renin in isolation (IC50 = 1.0 nM) and in a
functional setting (PRA IC50 = 13 nM) compared to the prototype
1a (renin IC50 = 3.1 nM, PRA IC50 = 8.4 nM). Although
compounds bearing longer alkyl linkers (3d, 3e) are slightly less
potent (3-4 fold) compared to 3c, their significant binding reflects
the conformational flexibility inherent in the alkyl groups.
Conversely, analogues projecting the critical amino group
through a C1C2 alkyl chain (3a, 3b) displayed substantially
reduced activity (>50-fold), suggesting that these changes force a
disrupted binding wherein the amino-Asp, biphenyl-S1/S3, and
Figure 1. Biphenylpiperidinylcarbinol renin inhibitors.
Each analogue required for the study could be accessed from
intermediates 2a and 2b, which were synthesized as described
previously (Scheme 1).3 The tertiary alcohol was synhesized as a
1:1 mixture of stereoisomers while the piperidine stereocenter
originated from (R)-Boc-nipecotic acid. Under certain reaction
conditions the stereopurity of the piperidinyl center was observed
to erode en route to 2a and 2b and attempts were made to avoid
this problem.5 While the enantiomeric purity of each analog is
presumed to be >95% based on starting material input, it should
be recognized that some compounds in this report could contain
enantiomeric or epimeric impurities based on the observed
lability of this stereocenter. Renin inhibitors 1, 3, 4, and 6 were
derived through HBTU-mediated coupling (HBTU, i-Pr2EtN,
DMF, 25 °C, 2 h) of piperidine 2 with N-Boc protected amino
acids followed by Boc removal (2M aq. HCl, CH3CN, 25 °C, 2
h). Urea-linked inhibitors (5) were prepared by converting 2a or
2b to an acylimidazolium adduct (CDI, CH2Cl2, Et3N, 25 °C, 18
h; MeI, 25 °C, 18 h) that was coupled with N-Boc protected
diamines (CH3CN, 50 °C, 18 h). Alternatively, the urea bond
could be formed by treating 2a or 2b with N-Boc protected
diamines (CH2Cl2, Et3N, 25 °C, 3 h) that had been activated as p-
nitrophenyl carbamates (p-NO2-C6H4-OCOCl, Et3N, 25 °C, 30
min).
carbamate-S3sp
accommodated.
interactions cannot be
simultaneously
Table 1. Effect of alkyl chain length.
Renina
IC50 (nM)
63
PRAb
IC50 (nM)
3800
Compd
R
3a
3b
3c
3d
3e
CH2NH2
CH2CH2NH2
CH2CH2CH2NH2
(CH2)4NH2
100
1.0 ± 0.5
3.2
ndc
13
100
120
(CH2)5NH2
2.0
aRenin values are presented as the mean of n = 2 measurements
with average SD of ± 0.3 pIC50; where n ≥ 3 was measured, values
are presented as mean ± SD. bPRA = plasma renin assay, values
are presented as the mean of n = 2 measurements with average SD
of ± 0.1 pIC50; ; cnd = not determined
Scheme 1.
Consistent with these results, an x-ray crystal structure6 of an
N-methyl propylamine containing compound (3p, Table 2) bound
to renin (Figure 2) demonstrates that the propyl chain binds in a
fully extended conformation ( > 150° for each bond) to center
the amine appendage between the two Asp carboxylates while
fully maintaining the renin binding contacts presented by other
elements of the molecule. In this binding mode, shorter alkyl
linkers would leave the amino group too distant from the
aspartates (≥4Å) for effective binding while longer linkers must
adopt unfavorable conformational angles to appropriately
position the amino group between the catalytic residues.
The biological activity of each analogue was assessed in assays
utilizing the human renin enzyme in buffer or in the presence of
human plasma (PRA, see Supporting Information). Activity
against P450s was routinely measured using Cypex bactosome
preparations and selected compounds were also assayed against
human liver microsomes (HLM) using midazolam as substrate to

Figure 2. X-ray structure of 3p bound to renin (2.6 Å).6 The
catalytic Asp32 and Asp215 are shown in green and the renin
molecular surface is in cyan.
Table 2. Effect of alkyl chain and nitrogen substitution.
Renina
IC50 (nM)
1.0 ± 0.5
PRAb
IC50 (nM)
13
ndc
540
450
nd
Compd
R1
R2
R3
R4
R5
3c
3f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
(S)-COOH
H
320
25
3g
3h
3i
H
H
(S)-CO2Me
H
H
H
(S)-CO2Bn
H
16
H
H
(S)-CONH2
H
630
20
3j
H
H
H
(S)-CH2OH
H
460
180
840
36
3k
3l
H
(R)-CH2OH
H
6.3
40
(S)-OH
H
H
H
H
H
H
H
H
H
H
3m
3n
3o
3p
3q
3r
OH
(S)-OH
C6H4Cl
H
H
2.0
1.3
0.8
1.3
630
2.5
H
H
H
nd
H
14 ± 2.4
20 ± 3
nd
H
Me
H
H
Me
H
H
(CH2)2OH
63
aRenin values are presented as the mean of n = 2 measurements with average SD of ± 0.3 pIC50 or where n ≥ 3 was measured, values are
presented as mean ± SD. bPRA = plasma renin assay, values are presented as the mean of n = 2 measurements with average SD of ± 0.1
pIC50 or where n ≥ 3 was measured, values are presented as mean ± SD; cnd = not determined
Having defined the optimal chain length for display of the
Asp-binding amino group, the effect of substitution of the propyl
chain was examined. In keeping with our intent to reduce the
lipophilicity and synthetic complexity of the inhibitors, polar
substituents that were readily accessible were predominately
surveyed (Table 2). In all cases tested, substitution at R1 and R3
produced significant reductions in renin inhibition (3f-3o, IC50 =
6630 nM) – a result that, in hindsight, is not unexpected given
that our subsequent structural analysis (Figure 2) of this series of
ligands indicates that the R1 and R3 substituents point inward
toward the hydrophobic S1 pocket of renin. In this context, it is
noteworthy that lipophilic groups at R3 (e.g. 3g, IC50 = 25 nM) are
tolerated more than polar groups of similar size (e.g. 3i, IC50 =
630 nM). In contrast, substituents at R2 are expected to project
away from the binding site toward solvent, and consistent with
this binding mode, the analogue bearing an R2 hydroxyl group
(3m) exhibited only a 2-fold reduction in renin potency compared
to 3c. Based on the structural analysis of 3p bound to renin
(Figure 2), it was apparent that one stereoisomer would more
readily project its attachment toward solvent, and as a result
compound 3n bearing the (S)-OH group was synthesized and, as
anticipated, it proved to be the more active isomer as it displayed
activity (renin IC50 = 1.3 nM) equivalent to 3c.

A retrospective interpretation of the binding mode of 3n was
derived from an x-ray crystal structure6 of the compound bound
to the renin active site. Of note, the Asp-binding aminoalkane
assumes a slightly altered orientation wherein the plane of the
propyl chain is nearly orthogonal to the propyl chain of 3p in its
two Asp carboxylates, and this result underscores the importance
of the interaction in stabilizing the renin-ligand complex.
Extension of the methyl group (e.g. 3r) produced a modest
reduction (2-fold) in renin inhibition, and this result, which has
also been observed in other compounds of this class,3 can be
attributed to the fact that the additional atoms must orient away
from the wall of the binding pocket formed by Gly34 forcing a
mildly destabilizing gauche conformation within the
dialkylamino chain (Figure 3c).
Encouraged by the activity of 3p which utilizes a secondary
amine Asp-binding moiety and computational methods that
identified piperidines as surrogates for the cyclopentylamine
moiety (see Supporting Information), an exploration of
endocyclic amine replacements for this functionality was
conducted (Table 3). Similar to observations with the acyclic
series, the optimal distance between the piperidinamide core of
the molecule and the Asp-binding nitrogen is 3-4 carbon atoms,
as exemplified by compounds 4d (renin IC50 = 2.0 nM, PRA IC50
= 40 nM) and 4e (renin IC50 = 1.6 nM, PRA IC50 = 23 nM) which
respectively bear the CH2-3-piperidinyl and CH2-4-piperidinyl
groups and bind renin with efficiencies comparable to that of 3p
(renin IC50 = 1.3 nM, PRA IC50 = 20 nM). Departure from the
optimal distance in this series leads to more pronounced
reductions (>50-fold) in renin potency as a result of the reduced
conformational flexibility and larger size of the saturated
heterocycles compared to the simple alkylamines. An additional
consequence is that the positioning of the cyclic group upon the
alkyl linker is critical as exemplified in the series 4d (IC50 = 2.0
nM), 4c (IC50 = 6.3 nM), and 4f (IC50 = 126 nM), which each
present the nitrogen at a distance 3 atoms beyond the carbonyl
group.
renin-bound conformation (Figure 3a).
This alternative
orientation, which is accommodated without affecting other
critical binding elements through a slight shift in the position and
angle of the piperidinamide group, more effectively directs the
hydroxyl group toward solvent and away from the hydrophobic
interior of the binding site (Figure 3a). More importantly, the
binding mode of 3n is accessible due to its lack of an N-Me
group, which would induce an energetically unfavorable fully
eclipsed (synperiplanar) conformation in the terminal region of
the aminoalkane as compared to the eclipsed (anticlinal)
conformation observed about the N-Me region of 3p in its renin-
bound orientation. Finally, the bound conformation of 3n allows
its hydroxyl group to maintain hydrogen bonds with its
neighboring carbonyl and amino groups forming a bicyclic
hydrogen-bonded structure (Figure 3b), which apparently
contributes productively to its binding to renin since disrupting
this pre-organized hydrogen-bonded network via O-methylation
produces a 3-fold reduction in activity (compare 3t, IC50 = 2.0
nM and 3u, IC50 = 5.0 nM, Table 4).
An x-ray crystal structure6 of 4e bound to renin was obtained
(Figure 4), and as expected from the structure-function results,
the CH2-4-piperidinyl group fits satisfactorily within the active
site without inducing unfavorable steric interactions or disturbing
the other binding elements within the molecule. In order to
adequately position its nitrogen atom between the two Asp
groups and simultaneously maintain the hydrogen bond with
Ser76 that anchors its carbonyl oxygen, the CH2-4-piperidinyl
group adopts a bisected conformation about its COCH2 bond,
thereby turning the piperidine inward to enable its interaction
with Asp32. This conformational feature is essential for
maximizing the potency of the endocyclic amine inhibitors as
those analogues which contain the methylene linker required to
allow this turn are exceptionally potent (4d, 4e, 4i, IC50 < 2 nM),
whereas those that lack this flexibility show reduced activity (e.g.
4c, IC50 = 6.3 nM).
More definitive support for the importance of the bisected
bond angle induced in compound 4e came by way of examining
the activity of several urea-linked Asp-binding alkylamines
(Table 3). Each of these compounds (5a-e) is unable to access
the bisected conformation observed for 4e, as the CONR1R2
bond is locked in an eclipsed orientation by virtue of the sp2-
character of the urea nitrogen. Accordingly, the direct analogue
of 4e exhibited a dramatically (>300-fold) reduced potency (5d,
IC50 = 500 nM) reflecting its inability to effectively bridge both
active site carboxylates. Conversely, urea-based analogues of
compounds that either lack the conformational flexibility of 4e
(e.g. 5c) or those that include additional rotatable bonds that may
overcome the limitations imposed by the urea bond angle (5a, 5b,
5e) display only modest reductions (1.35 fold) in their ability to
bind renin as compared to their amide-based counterparts (i.e.
4c, 3c, 3p, 4g, respectively).
Figure 3. (A) X-ray structure of 3n (cyan) bound to renin (3.2 Å)
in overlay with 3p (orange).6 (B) Bicyclic hydrogen-bonded
network of 3n. (C) Proposed binding mode of 3r.
A small set of analogues were synthesized to investigate the
effect of N-alkylation on renin potency in the newly developing
N-alkylamine series (3p-r, Table 2). N-methylation produced
3p, and the modification had little effect on potency against renin
(renin IC50 = 1.3 nM, PRA IC50 = 20 nM) but this alteration
provided a 2-fold reduction in Cyp3A4 inhibition (Table 4).
Although the origin of this effect is unknown, the result is
consistent with destabilization of a potential N-Fe interaction
between the amino group and the P450 heme cofactor. Within
renin, the methyl group is accommodated (Figure 2) without
interfering with the Asp binding via a shift in the orientation of
the propyl chain (see discussion above). While this shift induces
unfavorable conformational effects in 3p upon binding to renin
(e.g. Me-H eclipsing and twist-boat vs. chair piperidine), the
methyl group serves to shield the Asp-amine electrostatic
interaction from solvent, thereby compensating for these
energetic losses. N,N-dimethylation (3q) produced a substantial
reduction (500-fold) in renin activity, as anticipated, given that
such a modification would disrupt the observed bridging of the

5c
5d
5e
1-piperazinyl
Cl
Cl
Cl
2.0
500
100
170
nd
NH-(4-piperidinyl)
NHCH2-(4-piperidinyl)
Table 3. Endocyclic amines and urea-linked alkylamines.
nd
aRenin values are presented as the mean of n = 2 measurements
with average SD of ± 0.3 pIC50 or where n ≥ 3 was measured,
values are presented as mean ± SD. bPRA = plasma renin assay,
values are presented as the mean of n = 2 measurements with
average SD of ± 0.1 pIC50 or where n ≥ 3 was measured, values
are presented as mean ± SD; cnd = not determined
Renina
IC50 (nM)
2000
PRAb
IC50 (nM)
ndc
Compd
R
X
4a
4b
4c
4d
4e
4f
2-piperidinyl
3-piperidinyl
F
F
F
F
F
F
F
F
F
F
F
F
F
320
6.3 ± 3.5
2.0
nd
102
40
4-piperidinyl
CH2-(3-piperidinyl)
CH2-(4-piperidinyl
(CH2)2-(2-piperidinyl)
(CH2)2-(4-piperidinyl)
2-morpholino
1.6
23
126 ± 40
80
nd
4g
4h
4i
nd
1000
1.6
nd
Figure 4. X-ray structure of 4e bound to renin (2.9 Å).6 The
catalytic Asp32 and Asp215 residues are shown in green and the
renin molecular surface is in cyan.
CH2-(2-morpholino)
3-pyrrolidinyl
24 ± 2
540
nd
4j
25
4k
5a
5b
CH2-(2-pyrrolidinyl)
NHCH2CH2NH2
NHCH2CH2NHMe
800
3.2
150
120
6.3
Table 4. Comparative analysis of selected analogues.
Renina
IC50 (nM)
PRAb
IC50 (nM)
Cyp3A4c
IC50 (nM)
Selectivity
(fold)d
Compd
R
X
cLogP
3.83
1a
Cl
3.1
0.6
8.4
3.3
34
11
6a
3c
F
F
90
3.51
3.19
2.15
4.10
3.78
3.46
2.45
3.26
150
240
220
82
1.0 ± 0.5
2
13
240
440
49
3m
6b
3s
F
36
Cl
Cl
F
0.6
4.3 ± 1.4
16
1.0
140
560
840
480
140
430
420
96
3p
3t
1.3
20 ± 3
29
F
2.0
3u
F
5.0
50
aRenin values are presented as the mean of n = 2 measurements with average SD of ± 0.3 pIC50 or where n ≥ 3 was measured, values are
presented as mean ± SD. bPRA = plasma renin assay, values are presented as the mean of n = 2 measurements with average SD of ± 0.1
pIC50 or where n ≥ 3 was measured, values are presented as mean ± SD; cCyp3A4 values are from a single measurement; dselectivity =
Cyp3A4 IC50 / Renin IC50
In reflecting on the significant (17-fold) reduction in P450 inhibition achieved through replacing the cyclopentylamine group (1a,

Cyp3A4 IC50 = 34 nM) with an N-methylpropylamine (3p, Cyp3A4 IC50 = 560 nM) we recognized that application of our in house
ADMET rules of thumb to address this liability (via reducing lipophilicity) during analogue design had been successful.7 As it was
clear that there were multiple contributing factors leading to the profile displayed by 3p, a comparative analysis of key analogues in
this series was conducted to assess the magnitude of each effect (Table 4). Upon segregating analogues based on the presence or
absence of an N-methyl group, it was evident that their P450 activity was closely correlated with lipophilicity8 (i.e. cLog P, Table 4)
and that N-methylation also consistently provided reduced P450 inhibition (1.9 fold on average) in the series despite its undesirable
effect on clog P (cLog P = 0.27). Apparently, the destabilization of an interaction between the basic nitrogen and Cyp3A4
induced by the N-Me group outweighs any binding enhancement resulting from the lipophilic character it brings to these
compounds. The average contributions of each element in moderating P450 inhibition through reduction in lipophilicity were
quantified as 3.4-fold for Cl→F (cLog P = 0.32), 2.8-fold for C5H8→C3H6 (cLog P = 0.32), and 1.7-fold for C3H6→C 3H6O (cLog P =
1.03). Notably, the polarity increase accompanying the latter change (C3H6→C3H6O, PSA = 20 Å2) is not a major contributor to
the
reduced P450 inhibition since the 1.7-fold drop in Cyp3A4 activity is consistent with other losses observed upon lipophilic
reductions and compound 3u, which contains a similar polarity increase (PSA = 9 Å2) also demonstrates a potency against
Cyp3A4 expected based on its cLog P value alone. These observations mirror those detailed by other investigators and provide
further support for the notion that binding to Cyp3A4 is predominately driven by lipophilic forces.9 Each of the modifications
detailed here have little effect on renin activity, and as a result, increased selectivity (up to 40-fold) for renin over Cyp3A4 is
observed for each of these key analogues.
Compound 3p is a potent renin inhibitor that displays adequate levels of selectivity (430-fold) for renin over Cyp3A4 in isolated
enzyme assays, and the selectivity is even more pronounced (1000-fold) when activity is measured in the more relevant functional
settings (PRA IC50 = 20 nM, HLM IC50 = 20,000 nM). Based on structure-function results, the origin of the moderated P450
inhibition can be attributed primarily to the reduced lipophilicity of 3p compared to 1a. Like other renin inhibitors, compounds in
the biphenyl-piperidinylcarbinol series suffer from poor oral bioavailability in animals and addressing this limitation will be
necessary to identify new medicines for hypertension.
Acknowledgments
We gratefully acknowledge David Claremon and Jing Yuan of Vitae Pharmaceuticals for helpful discussions and Cathy Yuan and
Bahman Ghavimi for synthesis of 1a, 1b, and 6b.
References and Notes
1.
2.
3.
(a) O’Brien, E. Expert Opin. Investig. Drugs 2006, 15, 1269 (b) Staessen, J. A.; Li, Y.; Richart, T. Lancet 2006, 368, 1449. (c) Jensen, C.; Herold,
P.; Brunner, H. R. Nat. Rev. Drug. Disc. 2008, 7, 399.
(a) Yokokawa, F. Expert. Opin. Drug. Disc. 2013, 8, 673. (b) Webb, R. L.; Schiering, N.; Sedrani, R.; Maibaum, J. J. Med. Chem. 2010, 53,
7490.
(a) Yuan, J.; Simpson, R. D.; Zhao, W; Tice, C. M.; Xu, Z.; Cacatian, S.; Jia, L.; Flaherty, P. T.; Guo, J.; Ishchenko, A.; Wu, Z.; McKeever, B.
M.; Scott, B. B.; Bukhtiyarov, Y.; Berbaum, J.; Panemangalore, R.; Bentley, R.; Doe, C. P.; Harrison, R. K.; McGeehan, G. M.; Sing, S. B.;
Dillard, L. W.; Baldwin, J. J.; Claremon, D. A. Bioorg. Med. Chem. Lett. 2011, 21, 4836. (b) Tice, C. M.; Xu, Z.; Yuan, J.; Simpson, R. D.;
Cacatian, S. T.; Flaherty, P. T.; Zhao, W.; Guo, J.; Ishchenko, A.; Singh, S. B.; Wu, Z.; Scott, B. B.; Bukhtiyarov, Y.; Berbaum, J.; Mason, J.;
Panemangalore, R.; Cappiello, M. G.; Muller, D.; Harrison, R. K.; McGeehan, G. M.; Dillard, L. W.; Baldwin, J. J.; Claremon, D. A. Bioorg.
Med. Chem. Lett. 2009, 19, 3541. (c) Jia, L.; Simpson, R. D.; Yuan, J.; Wu, Z.; Zhao, W; Cacatian, S.; Tice, C. M.; Guo, J.; Ishchenko, A.; Sing,
S. B.; Wu, Z.; McKeever, B. M.; Bukhtiyarov, Y.; Johnson, J. A.; Doe, C. P.; Harrison, R. K.; McGeehan, G. M.; Dillard, L. W.; Baldwin, J. J.;
Claremon, D. A. ACS Med. Chem. Lett. 2011, 2, 747.
4.
5.
For a description of the renin S1/S3 binding pocket see (a) Rahuel, J.; Rasetti, V.; Maibaum, J.; Rueger, H; Goschke, R.; Cohen, N.-C.; Stutz, S.;
Cumin, F.; Fuhrer, W.; Wood, J. M.; Grutter, M. G. Chem. Biol. 2000, 7, 493. (b) Wood, J. M.; Maibaum, J.; Rahuel, J.; Grutter, M. G.; Cohen,
N.-C.; Rasetti, V.; Ruger, H.; Goschke, R.; Stutz, S.; Fuhrer, W.; Schilling, W.; Rigollier, P.; Yamaguchi, Y.; Cumin, F.; Baum, H.-P.; Schnell,
C. R.; Herold, P.; Mah, R.; Jensen, C.; O’Brien, E.; Stanton, A.; Bedigian, M. P. Biochem. Biophys. Res. Commun. 2003, 308, 698.
During synthesis of 2b the stereochemistry of the ketone intermediate below was found to be racemic when the reaction mixture was allowed to
warm and stand overnight at 25 ºC. No loss of enantiopurity was observed when the reaction mixture was quenched at 78 ºC.

6.
7.
8.
Coordinates for the X-ray co-crystal structures were deposited in the PDB. Renin-3p (5V8V), Renin-3n (5VRP), Renin-4e (5VPM).
Gleeson, M. P. J. Med. Chem. 2008, 51, 817.
For a review of the relationship between lipophilicity and Cyp3A4 binding see Lewis, D. A.; Jacobs, M. N.; Dickins, M. Drug Disc. Today 2004,
9, 530 and ref. 6.
9.
Smith, D. A.; Ackland, M. J.; Jones, B. C.. Drug Disc. Today 1997, 2, 406 and 479.
Supplementary Material
Experimental details for biological assays and computational chemistry and table of statistics for x-ray crystal structures.

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Discovery of renin inhibitors containing a
simple aspartate binding moiety that imparts
reduced P450 inhibition
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Brian G. Lawhorn, Tritin Tran, Victor S. Hong, Lisa A. Morgan, BaoChau T. Le, Mark R. Harpel, Larry Jolivette, Elsie
Diaz, Benjamin Schwartz, Jeffrey W. Gross, Thaddeus Tomaszek, Simon Semus, Nestor Concha, Angela Smallwood,
Dennis A. Holt, Lara S. Kallander